PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is characterized by inflammation of the central nervous system (CNS) primarily caused by autoreactive CD4 T cells. It is well documented that myelin-specific T cells, especially Th1 cells and Th17 cells, are important in the initiation of tissue inflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. A subset of CD4 T cells called CD4+CD25+ regulatory T cells (Tregs) that express Forkhead box P3 (Foxp3) can control autoimmune responses. During EAE development, Tregs enter the inflammation site in the CNS but are unable to suppress autoreactive CD4 T cells. It remains elusive, however, how Tregs are regulated during CNS inflammation. Our laboratory preliminary results indicate Tregs in the absence of STAT3 are capable of infiltrating CNS more effectively and therefore reduce chronic inflammation and EAE symptoms better than Tregs in the presence of STAT3. The following specific aims are proposed to elucidate the pathological role of STAT3 in the regulation of Tregs? function and the underlying mechanisms, and to understand the regulatory molecules of STAT3 activation in Tregs during CNS inflammation. Aim 1: To determine the impact of STAT3 expression on regulatory T cell function during CNS inflammation. Aim 2: To define the mechanism by which STAT3 expression in Tregs prevents CNS accumulation of Tregs during inflammation. Aim 3: To determine the environmental cues mediating STAT3 activation for Tregs during CNS inflammation. Collectively, these studies are designed to provide new information regarding the cellular mediators of CNS inflammation during EAE and will help to define the properties and molecular regulators that control the development of Tregs during CNS inflammation. Our overarching goal is to understand the regulatory network of inflammatory molecules and Tregs in promoting chronic inflammatory disorders, such as MS. Such data will help to identify molecular targets that can be used for potential therapeutic strategies for the treatment of autoimmune disease.